Peroxisome Proliferator Activated Receptors (PPAR""s) are members of the nuclear hormone receptor super family, which are ligand-activated transcription factors regulating gene expression. Various subtypes thereof have been identified and cloned. These include PPARxcex1, PPARxcex2 (also known as PPARxcex4), and PPARxcex3. There exist at least two major isoforms of PPARxcex3. While PPARxcex31 is ubiquitously expressed in most tissues, the longer isoform PPARxcex32 is almost exclusively found in adipocytes. In contrast, PPARxcex1 is predominantly expressed in the liver, kidney and heart. PPAR""s modulate a variety of body responses including glucose- and lipid-homeostasis, cell differentiation, inflammatory responses and cardiovascular events.
Diabetes is a disease in which a patient""s ability to control glucose levels in blood is impaired, because he has partially lost the ability to respond properly to the action of insulin. In type II diabetes (T2D), often referred to as non-insulin dependent diabetes mellitus (NIDDM), which afflicts 80-90% of all diabetic patients in developed countries, the Isles of Langerhans in the pancreas still produce insulin. However, the target organs, mainly muscle, liver and adipose tissue, exhibit a profound resistance to insulin stimulation, and the body compensates by producing unphysiologically high levels of insulin. In later stage of disease, however, insulin secretion decreases due to exhaustion of the pancreas. In addition to that T2D is a metabolic-cardiovascular disease syndrome. Among the comorbidities associated with T2D are for example insulin resistance, dyslipidemia, hypertension, endothelial dysfunction and inflammatory atherosclerosis.
Current first line treatment for diabetes generally involves low fatxe2x80x94and glucosexe2x80x94diet and exercise. However, compliance can be moderate and as the disease progresses, treatment with hypoglycemic drugs, e.g. sulfonylureas or metformin, becomes necessary. A promising new class of drugs has recently been introduced that resensitizes patients to their own insulin (insulin sensitizers), thereby reverting blood glucose and triglyceride levels to normal, and thus abolishing, or at least reducing, the requirement for exogenous insulin. Pioglitazone (Actos(trademark)) and rosiglitazone (Avandia(trademark)) belong to the thiazolidinediones (TZD) class of PPARxcex3-agonists and were the first representatives that had been approved for NIDDM in several countries. These compounds, however, suffer from side effects including rare but severe liver toxicity (as seen with troglitazone), and they increase body weight in humans. Therefore, new, better and more efficacious drugs for the treatment of NIDDM are urgently needed. Recent studies provide evidence that a coagonism on PPARxcex1 and PPARxcex3 would result in compounds with enhanced therapeutic potential, i. e. such compounds should improve the lipid profile in addition to the normalization of glucose- and insulin-levels (Keller and Wahli: Trends Endocrin. Metab. 1993; 4:291-296, Macdonald and Lane: Current Biology Vol.5 pp.618-621 (1995)). Recent observations suggest furthermore that there is an independent PPARxcex1 mediated effect on insulin-sensitzation that could result secondary to the reduction in lipids (Guerre-Millo et al; J Biol Chem2000; 275: 16638-16642). Consequently, the incorporation of PPARxcex1 activity into PPARxcex3 agonists is expected to give rise to more efficacious drugs for the treatment and/or prevention of diabetes.
The present invention provides compounds of the formula (I) 
wherein
X is N and Y is S; or
X is S and Y is N;
R1 is aryl or heteroaryl;
R2 is hydrogen, lower-alkyl or fluoro-lower-alkyl;
R3, R4, R5 and R6 independently from each other are selected from hydrogen, hydroxy, lower-alkenyl, halogen, lower-alkyl, fluoro-lower-alkyl, hydroxy-lower-alkyl, lower-alkoxy-lower-alkyl, lower-alkoxy, fluoro-lower-alkoxy, hydroxy-lower-alkoxy, and lower-alkoxy-lower-alkoxy, wherein at least one of R3, R4, R5 and R6 is not hydrogen, or
R3 and R4 are bonded to each other to form a ring together with the carbon atoms to which they are attached, and R3 and R4 together are xe2x80x94CHxe2x95x90CHxe2x80x94Sxe2x80x94, xe2x80x94Sxe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94CHxe2x80x94CHxe2x80x94Oxe2x80x94, xe2x80x94Oxe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94CHxe2x80x94SHxe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94(CH2)3-5xe2x80x94, xe2x80x94Oxe2x80x94(CH2)2-3xe2x80x94 or xe2x80x94(CH2)2-3xe2x80x94Oxe2x80x94, and R5 and R6 are as defined above;
R7 is lower-alkyl, lower-alkoxy, lower-alkenyloxy, aryloxy or aryl-lower-alkoxy,
R8 is hydrogen or lower-alkyl;
R9 and R10 independently from each other are hydrogen, lower-alkyl, lower-alkenyl, cycloalkyl, phenyl or [1,3]dioxan-2-ethyl;
n is 1, 2 or 3;
and pharmaceutically acceptable salts and pharmaceutically acceptable esters thereof.